Abyl-azo-diaminosyridines ttseftll as bactericides and process of making



Reissued Apr. 23, 1929.

YORK. 1 m

This invention relates to compounds useful as medicines and to processes for their manufacture. It is more particularly directed to a class of compounds having bactericidal ac- 5 tionagainst various forms of bacteria, particularly the cocci; and processes for their manufacture.

The objects of the invention are to produce a series of compounds having a wide range of usefulness in destroying bacteria, which shall possess marked therapeutic value in treat ment of various diseases of the body; and to provide a simple, easily-practiced process for the production of such compounds.

The invention comprises as a new material a non-poisonous composition made-with d1- aminopyridine, having a bacteric'idalcharac: ter. The compositions comprised herein are more specifically defined hereinafter. The invention also comprises a process for producing a bactericide which comprises forming-a non-poisonous colloidal or semi-colloidal material with diaminopyridine. /Vhere colloidal material or colloidal solution is employed in'the claims it is intended to include lution. In accordance with the present invention, I have found that the simplest azodyes of 2-6 diaminopyridine, which may be expressed by the formula Aryl-N=N \N v NH: where the aryl may bean aryl group, with or without various-radicals attached to the ring,

such as phenyl-, para-ethyl-pherlyL, orthophenylazodiamino-pyridine, the latter having thefollowing formula I xzN NH:

have been known to be relatively nontoxic, While possessing specific bactericidal action, and they must be regarded as a new and char- UNITEDSTATES PATENT OFFI IWAN OSTROMISLENSKY, 0]! NEW YORK, N. Y., ASSIGNQR, BY MESNE ASSIGNMENTS,

TO THE PYRIDIUM CORPORATION, OF NEW YORK, N.

ABYL-AZO-DIAMINOPYRIDINES nearer. As nacrnnrcrnns 'rnn slum a semi-colloidal material or semi-colloidal sometaand para-tolyl-, phenetidyl and sulfopossess useful properties of semi-colloids, and I a Re. 17,281 cs.

Am rnoonss OF MAKING No Drawing. Original No. 1,680,108, dated August 7, 1928, Serial No; 676,855, filed November 24; 1923. Application for reissue filed March 1, 1929. Serial No. 343,834.

possesses a poisonous character. I have foundhowever that this poisonous character may be overcome by forming colloidal or semi-colloidal materials with diaminopyridine such as those substances mentioned above. I have discovered that, these substances exercise a marked specific'action not so much in cases of malaria as in infectious diseases generated by variousmicrobes. These substances are especially virulent in killing off various microbes of the cocci group, such as pneumostaphylo-, diplo-, streptoand gono-cocci, the generator of venereal sores (ulcus lnolle) etc.

\Vhilesuch bactericidal action is found often in a millionth dilution, these semi-colloidal and colloidal substances formed with diaininopyridine remain almost passive toward the intestinal flora of the human and animal bodies.

The following are some examples of the form in which the compounds may be administered:

1. A saturated 0.6% solution of phenylazodiaminopyridine hydrochloride is prepared in distilled water. This solution is prepared in boiling distilled water; in the presence of mineral 7 table salt, the solubility of the hydrochloride is sharply reduced. i

2. A supersaturated 3% fresh solution of hydrochloride in distilled Water. The solution should be made up just prior to use and grill keep without sedimentation for about one our.

3. A thin emulsion of phenylazodiaminopyridine hydrochloride in distilled water containing for example 10% of the base phenylazodiaminopyridine. This emulsion is made by means of quick and'even cooling salts such as ordinary down of the 10% solution of phenylazodiaminopyridine hydrochloride prepared by boiling this material in distilled water. The Voluminous mass originally obtained is filtered under pressure to remove free liquid. It is thereafter left to stand in aclosed vessel for 12 to 24 hrs. It should be throughly shaken before using.

4. A 510% salve of phenylazodiaminopyridine hydrochloride, in lanolin, Vaseline, resorbin, etc.

5. A salve of phenylazodiaminopyridine (for example 10%) in lanolin or other greases.

6. An alcohol solution of phenylazodiaminopyridine either as th'e base or as the hydrochloride. These materials dissolve more readily in alcohol than they do in water. A preferred percentage is about 3%.

7. For application in powder form, ground, dried, hydrochloride of phenylazoiami nopyridine.

8. Gelatine capsules containing varying amounts such as 0.20.5 grams of compound (hydrochloride) Clinical researches have shown results in vivo coinciding closely with results made in vitro. The medical properties'and bactericidity of the members of the group have been in accordance with my experience most marked in the following members; phenyl-, paraethylphenyl-,ortho-,1netaand para-tolyl and para-ethoxy-azodiaminopyridine. I have not found that the benzidine azodycs of diaminopyridine have the specific medical properties of the other materials described herein. These benzidine azodyes both in the form of salts and in the free state dissolve with great difficulty even in boiling water. The compositions may be applied in various diseases and the following are some of the specific instances where it has been found effective:-In cases of ulcus corneee serpens, in various kinds of conjunctivis (purulent), in ulcus. molle (chancro-id), in furunculosis (boils) and in various cutaneous diseases of an infectious character, such as sties and pimples. It has also been applied prophylactically for washing fresh and infected Wounds and burns, as well as in cases of'ti'auma, where iodine has been indicated as an antiseptic. Its bactericidal character has been fully demonstrated by the applications mentioned.

In those cases where the focus of the disease can be reached by the composition a checking of the infection is rapidly accomplished. I have found that the composition is effective except in diseases generated by the intestinal flora. The use of the material is not accompanied by local or general reaction in the patient and can be introduced into the diseased organizism in many ways, name- 1 intraveneously, hypodermically, through t e mouth, etc. i

The following is a preferred process for manufacture of a composition in accordance with the invention:

Diaminopyridine is linked with diazotized paratoluidine and purified. Diazotization may be accomplished in the usual manner. Specifically a solution of 1.18 kilograms of freshly-distilled para toluidine in a mixture of 2.6 litres of fuming hydrochloric acid (specific gravity. 1.19) with 80-100 litres of Water is prepared and cooled with ice. To this 740 gms. of sodium nitrite dissolved in 20 litres of water is added'in small quantities, shaking up this mixture quite often the while. The product obtained is poured into a solution of 1335 gms. of diamino-pyridine in 13350 cc.

of, 10% hyrdochlorio acid, the mixture being stirred all the while. In order to neutralizethe excess of hydrochloric acid, an aqueous saturated solution of sodium acetate is add ed to the general mixture until a weak acid reaction on Congo paper is obtained. The mixture is then left to stand for several hours at room temperature, during which time a separation of fine crystals of the hydrochloric acid salts of para-tolyl-azo-diamino-pyridine takes place.

The resulting material para tolylazodiaminopyridine should be purified. Purification by crystallization from hot water usually leaves mineral salts and particularly sodium chloride which interfere with the use of the material for hypodermic and-intravascular injections. Furthermore, simple purification by such crystallizations from hot water produces a substance whose solubility in cold water is abnormally low. In order to purify the substance to make it suitable for hypodcrrnic and intravascular injections as well as to increase its solubility, the para tolylazodiaminopyridine hydrochloride is treated with a 510% solution of ammonia at ordinary temperature. Basic free needles of a yellowish golden color separate and are carefully washed in a large amount ofdistilled water at a temperature just below its boiling point. The washed needles so obtained are then-carefully heated in distilled water containing the theoretical amount of hydrochloric acid for that conversion. In order to make sure that no mineral acid then remains the preparation is recrystallized from hot distilled water. i r

In place of toluidine, aniline may be substituted, and upon diazotization in acid solution and coupling with 26-diamino-pyridine, phenyl-azo-diamino-pyridine is produced.

Sulphonic acids of the compounds N/H: may be obtained by heating with fuming sul phuric acid. As an example of this process 1 part of phenylazodiaminopyridine was ,is meant any phenyl group which can contain any radical such as, carboxylic, nitro group, iodine, hydroxy group, amino group,

nitrile GEN, and the like.

As many apparently widely difi'erent embodiments of this invention may be made without departing from the spirit thereof, it will be understood that I do not intend to limit myself to the/ specific embodiment herein set forth except as indicated in the appended claims.

What is claimed as new is 1. A medicinal substance including arylated azotized diamino-pyridines, prepared for use in the treatment of germ infections.

2. A medicinal preparation including a substance non-toxic in approved dosage having the general formula i NH:

Aryl-N=N L \\N V NH:

prepared for use in the treatment of germ infections. 7

3. As a medicinal substance, phenylazodiaminopyridine hydrochlorides crystallized in the form of dark red needles, soluble in watervto form a 1.5% solution at 16 (1,

prepared foruse in the treatment of germ infactions.

4. A process for producing a medicinal substance for use in the treatment of gem infections, which comprises diazotizing an arcmatic amine, coupling the diazotized amine with 26 diaminopyridine to obtain an arylazo-diaminopyridine and purifying to re move the harmful by-products.

6. A process for producing a medicinal substance for use in the treatment of germ infections, which comprises dlazotizlng an1- line, coupling the diazotized aniline with 26 diaminopyridine, forming a soluble acid salt, purifying by decomposing the acid salt by treatment with an alkali material, removing by-products, treating the purified basic material thus produced to form again an acid salt of phenyl-azo-diaminopyridine.

7 The process of rendering innocuous, various forms of microbes, particularly those of the cocci group, which consists in subjecting them to an arylated azotized diamino-pyridine in divided condition.

8. The process of rendering innocuous, Various forms of microbes, particularly those of the cocci group, which consists in subjecting them to arylated azotized diamino-pyridine hydrochlorides prepared forthe purpose in divided condition.

9. The process of renderinginnocuous, various forms of microbes, particularly those of the cocci group, which consists in subjecting them to a suspension of divided arylated azotized diaminopyridine prepared for the purpose.

10. A medicinal substance prepared for use in the treatment of germ infections, including an arylated azotized diamino-pyridine finely divided and in segregated masses of suitable dosage.

Signed. at New York, in the county and State of New York, this 15th day of Febru ary A. D. 1929.

1WAN OSTROMISLENSKY. 

